Obesity is pandemic and worsening in developed countries (see e.g., Mokdad, A. H., et al., J. Am. Medical Assoc. 284:1650 (2000), the disclosure of which is incorporated herein by reference). Obesity contributes importantly to the metabolic syndrome (see e.g., Grundy, S. M., Endocrine 13:155 (2000) (hereinafter, “Grundy, 2000”); Bergman, R. N., et al., Journal of Investigative Medicine 49:119 (2001) (hereinafter, “Bergman, 2001”), the disclosures of which are incorporated herein by reference), a disorder characterized by hypertension, insulin resistance and hyperlipidemia (Grundy, 2000; Bergman, 2001). The metabolic syndrome in turn contributes to heart and vascular disease (see e.g., Colditz, G. A., Medicine & Science in Sports & Exercise 31:S663 (1999), the disclosure of which is incorporated herein by reference), and to the accelerating epidemic of end stage renal failure (see e.g., Hall, W. D, et al., American Journal of the Medical Sciences 313:195 (1997); Hall, J. E. et al., Annals of the New York Academy of Sciences 892:91 (1999), the disclosures of which are incorporated herein by reference). Unfortunately, pharmacological management of obesity has caused, rather than attenuated, cardiovascular disease. For example, a popular phentermine/fenfluramine combination produces valvular heart disease (see e.g., Lepor, N. E., et al., American Journal of Cardiology 86:107 (2000), the disclosure of which is incorporated herein by reference), while another popular treatment option, phenylpropanolamine, causes stroke (see e.g., Kernan, W. N., et al., New England J. Med. 343:1826 (2000), the disclosure of which is incorporated herein by reference). Thus, drugs that prevent or treat obesity and its metabolic, vascular and renal sequelae, without adversely affecting the heart, are badly needed.
Several compounds have been reported to cause a reduction in body weight. For example, Oparil, S., et al., Circulation 95:1301 (1997), the disclosure of which is incorporated herein by reference, reported that 17β-estradiol caused a reduction in body weight of rats as well as vascular protection. However, adverse effects to using 17β-estradiol are that undesirable feminizing effects are caused in males and there is increased risk of breast and uterine cancer in females due to the estrogenic effect of 17β-estradiol.
In that there appears to be a linkage between obesity, metabolic syndrome, diabetes, and vascular and renal disorders, it is important and desirable to be able to treat several or all of these conditions simultaneously with one pharmacological agent regardless of the gender of the individual.